Inhibition of p38 mitogen-activated protein kinase alters microRNA expression and reverses epithelial-to-mesenchymal transition

Antoon,James  W.; Nitzchke,Ashley   M.; Martin,Elizabeth  C.; Rhodes,Lyndsay  V.; Nam,Seungyoon; Wadsworth,Scott; Salvo,Virgilo  A.; Elliott,Steven; Collins-Burow,Bridgette; Nephew,Kenneth  P.; Burow,Matthew  E.

doi:10.3892/ijo.2013.1814

Inhibition of p38 mitogen-activated protein kinase alters microRNA expression and reverses epithelial-to-mesenchymal transition

Authors:
- James W. Antoon
- Ashley M. Nitzchke
- Elizabeth C. Martin
- Lyndsay V. Rhodes
- Seungyoon Nam
- Scott Wadsworth
- Virgilo A. Salvo
- Steven Elliott
- Bridgette Collins-Burow
- Kenneth P. Nephew
- Matthew E. Burow
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Affiliations: Department of Medicine, Section of Hematology and Medical Oncology, Tulane University School of Medicine, New Orleans, LA 70112, USA, Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Bloomington, IN 47405, USA, Johnson & Johnson Pharmaceutical Research & Development, Raritan, NJ 08869, USA
Published online on: February 8, 2013 https://doi.org/10.3892/ijo.2013.1814
Pages: 1139-1150
Copyright: © Antoon et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

Acquired chemoresistance and epithelial-to-mesenchymal transition (EMT) are hallmarks of cancer progression and of increasing clinical relevance. We investigated the role of miRNA and p38 mitogen-activated protein kinase (MAPK) signaling in the progression of breast cancer to a drug-resistant and mesenchymal phenotype. We demonstrate that acquired death receptor resistance results in increased hormone-independent tumorigenesis compared to hormone-sensitive parental cells. Utilizing global miRNA gene expression profiling, we identified miRNA alterations associated with the development of death receptor resistance and EMT progression. We further investigated the role of p38 MAPK in this process, showing dose-dependent inactivation of p38 by its inhibitor RWJ67657 and decreased downstream ATF and NF‑κB signaling. Pharmacological inhibition of p38 also decreased chemoresistant cancer tumor growth in xenograft animal models. Interestingly, inhibition of p38 partially reversed the EMT changes found in this cell system, as illustrated by decreased gene expression of the EMT markers Twist, Snail, Slug and ZEB and protein and mRNA levels of Twist, a known EMT promoter, concomitant with decreased N‑cadherin protein. RWJ67657 treatment also altered the expression of several miRNAs known to promote therapeutic resistance, including miR‑200, miR‑303, miR‑302, miR‑199 and miR‑328. Taken together, our results demonstrate the roles of multiple microRNAs and p38 signaling in the progression of cancer and demonstrate the therapeutic potential of targeting the p38 MAPK pathway for reversing EMT in an advanced tumor phenotype.

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